B cells play a crucial role in the immune response and contribute to various autoimmune diseases. Recent studies have revealed abnormalities in the B cell receptor (BCR) repertoire of patients with ...autoimmune diseases, with distinct features observed among different diseases and B cell subsets. Classically, BCR repertoire was used as an identifier of distinct antigen-specific clonotypes, but the recent advancement of analyzing large-scale repertoire has enabled us to use it as a tool for characterizing cellular biology. In this review, we provide an overview of the BCR repertoire in autoimmune diseases incorporating insights from our latest research findings. In systemic lupus erythematosus (SLE), we observed a significant skew in the usage of VDJ genes, particularly in CD27
IgD
unswitched memory B cells and plasmablasts. Notably, autoreactive clones within unswitched memory B cells were found to be increased and strongly associated with disease activity, underscoring the clinical significance of this subset. Similarly, various abnormalities in the BCR repertoire have been reported in other autoimmune diseases such as rheumatoid arthritis. Thus, BCR repertoire analysis holds potential for enhancing our understanding of the underlying mechanisms involved in autoimmune diseases. Moreover, it has the potential to predict treatment effects and identify therapeutic targets in autoimmune diseases.
To stratify patients with mixed connective tissue disease (MCTD) based on their immunophenotype.
We analyzed the immunophenotype and transcriptome of 24 immune cell subsets from patients with MCTD, ...systemic lupus erythematosus (SLE), idiopathic inflammatory myopathy (IIM), and systemic sclerosis (SSc) from our functional genome database, ImmuNexUT (https://www.immunexut.org/). MCTD patients were stratified by employing machine learning models including Random Forest, trained by immunophenotyping data from SLE, IIM, and SSc patients. Transcriptomes were analyzed with gene set variation analysis (GSVA) and clinical features of MCTD subgroups were compared.
This study included 215 patients, including 22 patients with MCTD. Machine learning models, constructed to classify SLE, IIM, and SSc patients based on immunophenotyping, were applied to MCTD patients, resulting in 16 classified as SLE-immunophenotype and 6 as non-SLE-immunophenotype. Among MCTD patients, patients with the SLE-immunophenotype had higher proportions of Th1 cells 2.85% (interquartile range (IQR) 1.54-3.91) vs 1.33% (IQR 0.99-1.74) p= 0.027 and plasmablasts 6.35% (IQR 4.17-17.49) vs 2.00% (IQR 1.20-2.80) p= 0.010. Notably, the number of SLE-related symptoms was higher in patients with the SLE-immunophenotype 2.0 (IQR 1.0-2.0) vs 1.0 (IQR1.0-1.0) p= 0.038. Moreover, GSVA scores of interferon-α and -γ responses were significantly higher in patients with the SLE-immunophenotype in central memory CD8+ T cells, while hedgehog signalling was higher in non-SLE-immunophenotype patients in 5 cell subsets.
This study describes the stratification of MCTD patients based on immunophenotyping, suggesting the presence of distinct immunological processes behind the clinical subtypes of MCTD.
Abstract Objectives Unraveling the mechanisms underlying treatment response for targeted therapeutics in systemic lupus erythematosus (SLE) patients is challenging due to the limited understanding of ...diverse responses of circulating immune cells, particularly B cells. We investigated B lymphocyte dynamics during anti-BAFF treatment, utilizing longitudinal single-cell transcriptome data. Methods We conducted single-cell RNA sequencing on PBMCs in four Korean SLE patients before and after belimumab treatment at the following time points: 2 weeks, 1, 3, 6, and 12 months. Results Analyzing over 73 000 PBMCs, we identified 8 distinct subsets of B cells and plasmablasts and analyzed dynamic changes within these cell subsets: initial declines in naive and transitional B cells followed by an increase at three months, contrasted by an initial increase and subsequent decrease in memory B cells by the third month. Meanwhile, plasmablasts exhibited a consistent decline throughout treatment. B cell activation pathways, specifically in naive and memory B cells, were downregulated during the third and sixth months. These findings were validated at the protein level throughout the first four weeks of treatment using flow cytometry. Comparative analysis with bulk transcriptome data from 22 Japanese SLE patients showed increased NR4A1 expression six months post-belimumab treatment, indicating its role in restricting self-reactive B cells, thereby contributing to the biological responses of anti-BAFF treatment. Conclusion The observed B cell dynamics provided insights into the immunological mechanisms underlying the therapeutic effects of anti-BAFF in SLE patients. Furthermore, it underscores the need for research in predicting drug responses based on immune profiling.
There have been hundreds of reports on mutations in the
NLRP3
gene related to
NLRP3
-associated autoinflammatory disease, but few of these mutations have occurred as both germline and somatic mosaic ...mutations. In this case-based review, we report a 68-year-old man with an
NLRP3
-associated autoinflammatory disease. He developed secondary amyloidosis, including a renal and colorectal presentation in his 50 s. Sequencing of the
NLRP3
gene revealed an I574F somatic mosaic mutation, which has up to now only been reported in germline mutations. The patient was treated with canakinumab, which had great efficacy not only on the NLRP3-mediated inflammation, but also on the chronic renal failure and proteinuria provoked by secondary renal amyloidosis. To evaluate the effectiveness of canakinumab, we conducted a literature research on renal amyloidosis related to
NLRP3
-associated autoinflammatory disease treated with canakinumab. Although our patient had a relatively long medical history and greater amounts of proteinuria than other reported cases, canakinumab had great efficacy on renal impairment, in similar to other reported cases. Along with the first report of a late-onset I574F somatic mosaic mutation in
NLRP3
-associated autoinflammatory disease, this report demonstrates the effectiveness of canakinumab on renal amyloidosis, probably through the way that IL-1β blockade minimizes podocyte injury.
Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4
T cell subsets from 354 patients with ...autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3
CD4
effector memory T cell subset that expands with age, which we designated "age-associated T helper (T
A) cells." T
A cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of T
A cells, gene expression in T
A cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that T
A cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of T
A cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.
Despite evacuation on foot being recommended by authorities, evacuation in practice is assumed to include evacuation on foot and evacuation by car, as a certain amount of evacuation by car is to be ...expected. We developed a tsunami evacuation training application operating on smartphones and tablets, and a tsunami evacuation training simulator to evaluate the effect of this application. We then conducted an experiment in Nishio City to evaluate the application. We found that the subjects were able to quickly grasp the attention targets that were present near them but had difficulty grasping attention targets that were far away. This suggests that participants need to be trained repeatedly on distant objects of attention to be able to locate them instantaneously.
Disasters such as the Great East Japan Earthquake have highlighted the importance of tsunami evacuation awareness training that simulates mixed car and on-foot evacuations. A tsunami evacuation ...simulation was developed for car and on-foot evacuations that was then demonstrated at the “Nishio City Disaster Prevention College” event. The results of the questionnaire revealed that the simulation system was useful in teaching how to calmly deal with the evacuations; however, several issues need to be addressed, such as improving the controller and control system and reducing feelings of VR sickness. It was also suggested that repeated experiences were more effective in gaining a full understanding of the evacuation routes.
Disasters such as the Great East Japan Earthquake have highlighted the importance of tsunami evacuation awareness training that simulates mixed car and on-foot evacuations. A tsunami evacuation ...simulation was developed for car and on-foot evacuations that was then demonstrated at the “Nishio City Disaster Prevention College” event. The results of the questionnaire revealed that the simulation system was useful in teaching how to calmly deal with the evacuations; however, several issues need to be addressed, such as improving the controller and control system and reducing feelings of VR sickness. It was also suggested that repeated experiences were more effective in gaining a full understanding of the evacuation routes.
